Aldehydes and ketones of trifluoromethylfurans



United States Patent 3,439,000 ALDEHYDES AND KETONES 0FTRIFLUOROMETHYLFURANS Kenneth K. Wyckotf, Ronald E. Bambnry, and DavidM.

Tennent, Ashland, Ohio, assignors to Richardson-Merrell Inc., New York,N.Y., a corporation of Delaware No Drawing. Continuation-impart ofapplication Ser. No. 482,907, Aug. 26, 1965. This application Oct. 6,1965, Ser. No. 493,535

Int. Cl. C07d 5/26, 5/22; A61] 13/00 U.S. Cl. 260-3475 13 Claims Thisapplication is a continuation-in-part of our copending United Statespatent application Ser. No. 482,907, filed on Aug. 26, 1965, now U.S.Patent 3,405,163.

This invention relates to novel aldehyde and ketone derivatives oftrifluoromethylfurans. More particularly, this invention relates tocompounds of the formula wherein A is either hydrogen or an ester groupof the formula wherein R is alkyl, aryl, cycloalkyl or aralkyl and (a)in the case of aldehydes, either R or R is formyl and the remaining R orR" is hydrogen or aryl, whereas (b) in the case of ketones, either R orR" is alkylcarbonyl and the remaining R or R is hydrogen or aryl.

The aldehydes of this invention when A of Formula I is an ester groupcan be represented by the following Formula II:

wherein R is lower alkyl, aryl, cycloalkyl or aralkyl; either R or R" isformyl and the remaining R or R" is either hydrogen or a carbocyclicaryl, Illustrative of suitable groups as can be represented by R, therecan be mentioned: lower alkyl, i.e., alkyl having from 1 to 6 carbonatoms, and preferably alkyl having from 1 to 3 carbon atoms, e.g.,methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, etc.; carbocyclicaryls having 6 to 10 carbon atoms, i.e., phenyl or naphthyl; carbocyclicaralkyls of phenyl or naphthyl having from 7 to 14 carbon atoms, e.g.,benzyl, phenylethyl, phenylpropyl, a-naphthylmethyl, fi-naphthylethyl,etc.; and cycloaliphatics having from 3 to 6 carbon atoms such ascyclopropyl, cyclobutyl, cyclohexyl, etc. The R or R" which is notformyl can be hydrogen, phenyl or naphthyl and preferably hydrogen,particularly when R is formyl and R is lower alkyl. Illustrative ofaldehydes of the above Formula II there can be mentioned:4-carbomethoxy-S-trifluoromethyl-Z-furfural;4-carbethoxy-S-trifluoromethyl-Z-furfural;isopropyl-5-formyl-2-trifluoromethyl-3-furoate; phenyl 5-formy1-Ztrifluoromethyl-3-furoate; cyclohexyl5-formyL2-trifluoromethyl-3-furoate; benzylS-formyl-Z-trifluoromethyl-3-furoate; 4-carbethoxy-5-trifluoromethyl-3-furfural; n-amyl 4-formyl-2-trifiuoromethyl-3-furoate; phenyl4-formyI-Z-trifluoromethyl-3-furoate;

"ice

benzyl 4-formyl-2-trifluoromethyl-3-furoate;

cyclohexyl 4-formyl-2-trifluoromethyl-3-furoate;4-carbethoxy-3-phenyl-5-trifiuoromethyl-Z-furfural; 4-carbethoxy-3-(ct-naphthyl) -5-trifluoromethyI-Z-furfural;4-carbethoxy-2-phenyl-S-trifluoromethylfurfural;

phenyl 5-formyl-4-pheny1-2-trifluoromethyl-3-furoate'; and the like.

The ketones of this invention when A of Formula I is an ester group canbe represented by the following Formula III:

0 Formula III wherein: R represents the same groups recited for R in theFormula II aldehydes; one of R or R" is alkylcarbonyl of the formulawherein Z is alkyl of 1 to 5 carbon atoms, and the remaining R or R ishydrogen, phenyl or naphthyl. Preferably R is lower alkyl, R is hydrogenand R is alkylcarbonyl. Illustrative of ketones of the above Formula IIIthere can be mentioned:

ethyl 5-acetyl-Z-trifiuorornethyl-3-furoate;

butyl 5-acetyl-2-trifluoromethyl-3-furoate; isopropyl5-acetyl-2-trifluoromethyl-3-furoate; phenyl5-acetyl-2-trifluoromethy1-3-furoate; cyclohexyl5-acetyl-Z-trifluoromethyl-3-furoate; benzyl5-acetyl-2-trifluorornethyl-3-furoate;

ethyl S-propionyl-Z-trifiuoromethyl-3-furoate; ethyl4-acetyl-2-trifluoromethyl-3-furoate;

phenyl 4-acetyl-2-trifiuoromethyl-3-furoate; cyclohexyl4-acetyl-2-trifluoromethyl-3-furoate; benzyl-4-acetyl-2-trifluoromethyl-3-furoate;

ethyl 4-propionyl-2-trifiuoromethy1-3-furoate; ethyl5-acetyl-4-phenyl-2-trifiuoromethyl-3-furoate; ethyl4-acetyl-S-phenyl-Z-trifluoromethyl-3-furoate; ethyl5-acetyl-4-(ix-naphthyl)-2-trifluoromethyl-3-furoate; and the like.

The aldehydes of this invention when A of Formula I is hydrogen can berepresented by the following Formula 0 Formula IV wherein: R and Rrepresent the same R and R groups described in the Formula II aldehydes.Illustrative of aldehydes of the above Formula IV, there can bementioned:

5-trifluoromethyl-2-furfural; 5-trifluoromethyl-3-phenyl-2-furfural;5-trifiuoromethyl-3-furfural; 5-trifluoromethyl-2-phenyl-3-furfural; and5-trifiuoromethyl-3-(ct-naphthyl)-2-furfural.

The ketones of this invention when A of Formula I is hydrogen can berepresented by the following Formula V:

0 Formula V wherein: one of R and R" is alkylcarbonyl of the formulawherein Z is alkyl of 1 to 5 carbon atoms and preferably 1 to 2 carbonatoms and the remaining R or R" is hydrogen, phenyl or naphthyl.Illustrative of ketones of the above Formula V, there can be mentioned:2-acetyl-5- trifiuoromethylfuran; 2-propionyl-5-trifluoromethylfuran; 2acetyl 3 phenyl 5 -trifluoromethylfuran; 2 acetyl- 3 (a naphthyl) 5trifluoromethylfuran; 3 acetyl- 5 trifluomethylfuran; 3 propionyl 5trifluoromethylfuran; 3 acetyl 2 phenyl 5 trifluoromethylfuran; and thelike.

The aldehydes and ketones of this invention can be prepared byconventional techniques for the preparation of aldehydes and ketonesfrom aromatic compounds having a lower alkyl group substituted with oneor two halogen atoms on the carbon atom of the alkyl adjacent to thearomatic ring. Many such techniques generally involvedehydrohalogenation together with or followed by hydrolysis. Thehalogenated furan reactants employed in preparing the aldehydes andketones of this invention are describe in our copending application Ser.No. 493,534, filed concurrently herewith.

One method for preparing the aldehydes and ketones is by the reaction ofa monohalogenated furan reactant with an alkali metal salt of anitroalkane to prepare an intermediate Which is then hydrolyzed. This,as well as the other methods disclosed herein for the preparationof'aldehydes and ketones, is applicable whether A of Formula I is anester group or hydrogen and whether the compound, to be produced is aketone or an aldehyde. This reaction can be shown as follows:

O R H wherein A is hydrogen or an ester group i (CO-R) as described inthe Formula II compounds; R is the group II I wherein G is hydrogen oralkyl of l to 5 carbon atoms. In the above equation, the hydrogen shownon the furan rings' can be aryl as described in Formula II. Also, thefuran reactant can have the positions for R and hydrogen (or aryl)interchanged with each other and the resulting compounds would have thehydrogen (or aryl) and resulting carbonyl group in the interchangedpositions. A preferred method for effecting the above reaction is asfollows:

To the sodium salt of a nitroalkane (Z-nitropropane, nitrobutane,nitrocthane, etc.) suspended in an alcohol (ethanol, propanol, butanol,etc.) is added an equal molar quantity of the monohalogenated furancompound. The mixture is allowed to react within the range of 0 C. toreflux temperature until the pH drops to near neutrality. The alcohol isremoved by evaporation at reduced pressure, water is added to theresidue, and the residue partitioned between water and a solvent (ether,benzene,

chloroform, etc.) The organic phase is washed with aqueous base (2-5sodium or potassium hydroxide or 10% sodium carbonate, etc.). Afterdrying of the organic phase by a suitable reagent (sodium sulfate,magnesium sulfate, molecular sieves, etc.), the product is isolated byfractional distillation of the mixture. The product may also be isolatedat this point by converting it to a solid addition complex such as abisulfite complex, purifying the complex and finally regenerating thealdehyde from the complex.

A method which can be employed to prepare the aldehydes and ketones fromdihalogenated furans is illustrated below.

wherein A is hydrogen or an ester group as described for the Formula IIcompounds; R" is the group wherein each X is a halogen having an atomicnumber greater than 9, G is hydrogen or alkyl of 1 to 5 carbon atoms;and R is the group whreein G is hydrogen or alkyl of 1 to 5 carbonatoms. In the above equation the hydrogen shown on the furan rings can'be phenyl or naphthyl or R and of course the resulting R can be in theposition shown for hydrogen on the furan rings, in which case theposition shown for R and the resulting R in the above equation would besubstituted with hydrogen, phenyl or naphthyl. A preferred method foreffecting the above reaction is as follows:

A mixture of a dihalogenated furan, e.g.,5-trifluoromethyl-Z-dibromomethylfuran, water and a base (calciumcarbonate, barium hydroxide, calcium oxide) is heated with stirringuntil the hydrolysis is complete (1 to 10 hours). This may beascertained by any one of several analytical techniques such as vaporphase chromatography, thin layer chromatography, or by a test forpresence of active organic halide, etc. The aldehyde formed in thehydrolysis is then separated from the aqueous phase by extraction withan organic solvent or by steam distillation. Purification of thealdehyde maybe accomplished by distillation, vapor phase chromatography,column chromatography, conversion to a complex, etc.

Still another method for preparing the aldehydes and ketones of thisinvention is by the Sommelet reaction which consists of refluxing asolution of the haloalkyl reactant with hexamethylenetetramine inaqueous alcohol, or if the reactants are mixed in a non-aqueous solvent,they combine to form a quaternary ammonium salt which is decomposed bywater. This latter technique can be shown as follows:

wherein X is a halogen having an atomic number greater than 9; A ishydrogen or an ester group as described for the Formula II compounds;and G is hydrogen or alkyl of 1 to 5 carbon atoms. In the aboveequation, (a) the hydrogen shown on the furan ring can be phenyl ornaphthyl, or (b) the positions of the hydrogen (or the aryl) shown onthe furan rings and that of the -CHG and the resulting ll can beinterchanged so that the hydrogen (or aryl) is on the carbon atomadjacent to the heterocyclic oxygen. A preferred method for etfectingthis reaction is as follows:

The trifluoromethyl-halomethylfuran is treated with a molar equivalentamount of hexamethylenetetramine in an inert solvent (carbontetrachloride, chloroform, benzene, etc.). The mixture is refluxed forabout 2 hours and the salt which is formed is then isolated andhydrolyzed in an aqueous medium (50% acetic acid or 60% ethanolpreferred). Refluxing the mixture for one to two hours is usuallysufiicient to complete the hydrolysis. The aldehyde or ketone is thenisolated by standard procedures (extraction, steam distillation, complexformation, etc.).

The preparation of the halogenated trifiuoromethylfurans which are usedas reactants for the preparation of the aldehydes and ketones of thisinvention is described in our copending US. patent application Ser. No.493,534, filed concurrently herewith. Briefly, in a preferred process,they can be prepared by allylic halogenation by refluxingN-bromosuccinimide with .a solution of carbon tetrachloride and thecorresponding trifluoromethylfuran having a lower alkyl group in placeof one of the R' or R" groups of the Formula I compounds, whereas theremaining R or R" is hydrogen or aryl of from 6 to 10 carbon atomsOptionally, an activator such as dibenzoyl peroxide is added to improvethe bromination; also illumination of the refluxing mixture with anultraviolet source speeds up the reaction. Equal molar quantities of thebrominating agent and trifluoromethylfuran reactant are generallyemployed in preparing monobrominated derivatives, whereas two molarequivalents of the brominating agent are generally employed per moleequivalent of the trifluorotmethylfuran reactant in preparing thedibrominated derivatives. This reaction can be depicted as follows forthe preparation of monobrominated derivatives having a bromine atom onan alkyl group attached to the furan ring carbon atom adjacent to theheterocyclic oxygen and wherein R of Formula I is hydrogen.

wherein A is hydrogen or an ester group as described in Formula II, R"is lower alkyl, NBS is N-bromosuccinimide, S is succinimide and G ishydrogen or alkyl of 1 to carbon atoms. The hydrogen shown on the furanring in the above equation can also be phenyl or naphthyl; also theposition on the furan ring reactant of the hydrogen (or phenyl ornaphthyl) with that of R" and the resulting can be interchanged so thatthe reactants and resulting products have the hydrogen, phenyl ornaphthyl on the furan ring carbon atom adjacent to the heterocyclicoxygen.

A generic formula for the halogenated trifiuoromethylfurans used toprepare the aldehydes and ketones of this invention can be representedas follows:

6 wherein A is hydrogen or an ester group 0 ll CO-R wherein R has thesame meaning as R in the Formula II esters; either R or R is ahalogenated alkyl of the formula wherein each X is halogen having anatomic number greater than 9 and G is hydrogen or alkyl of 1 to 5 carbonatoms; and the remaining R or R is hydrogen, phenyl or naphthyl.

The trifluoromethylfuran reactants for preparing the halogenatedderivatives, wherein the compounds have an ester group, i.e., A in theabove Formula B is an ester, can be prepared by the cyclization, at atemperature of about C., of a trifluoromethy-l dione in contact with acatalytically effective quantity of an acid, e.g., sulfuric acid. Thisprocess together with the resulting compounds is more fully described inour copending patent application Ser. No. 493,534, filed concurrentlyherewith. The

process can be illustrated as follows:

0 R o 0 II I H H+ H CF -C-CH-CH-C-R" R0C-( J-(fi-R' rfi-0-R F3C-C C-R 0o FormulaA wherein R is lower alkyl, cycloa-lkyl or aryl as described inthe Formula 11 compounds; one of R and R" is lower alkyl; and theremaining R or R" is hydrogen, phenyl or naphthyl. The preparation ofthe dione reactant is described in our copending United States patentapplication Ser. No. 482,907, filed on Aug. 26, 1965. Briefly, thediones are prepared by reacting an alkali metal enolate salt of certaintrifluoroketo compounds with an a-haloketone in the presence of acatalytically effective quantity of an alkali metal iodide. The reactioncan be illustrated as follows:

wherein each of R, R and R" have the same meaning as in the aboveFormula A, X is a halogen such as bromine, and B is a strong alkalimetal base, e.g., sodium ethoxide.

The halogenated trifiuoromethylfurans used as reactants for thepreparation of the aldehydes and ketones of this invention are alsoderived from the esters of Formula A. The esters are first hydrolyzed tothe corresponding acid. The hydrolysis is effected by preparing analkali metal salt, e.g., with sodium hydroxide, of the ester of FormulaA and then converting the salt to the free furoic acid by contact with amineral acid, e.g., hydrochloric acid. The acid is then thermallydecarboxylated by heating at a temperature in the range of about C. to300 0., preferably in the presence of high boiling solvents such asquinoline together with a decarboxylation catalyst, e.g., copper oxide.The decarboxylated trifluoromethylfuran is then halogenated in the samemanner as that of the Formula A esters to produce the halogenatedtrifluoromethylfuran compounds used as reactants for the preparation ofthe Formula I compounds of this invention having hydrogen for the groupA. These halogenated 7 trifiuoromethylfuran reactants can be representedby the formula:

wherein one of R and R" is a monoor dihalogenated .group of the formulawherein each X is a halogen having an atomic number greater than 9 and Gis hydrogen or alkyl of 1 to carbon atoms and whereas the remaining R orR" is hydrogen, phenyl or naphthyl.

The aldehydes and ketones of this invention can be employed as theactive antibacterial constituent of disinfectant compositions for thecontrol of microorganisms such as: Bacillus subtilis; Pseudomonasaeruginosa; Salmonella typhimm'ium; Escherichia coli; Proteus mirabilis;Erysipelothrix insidiosa; Staphylococcus aureus; Streptococcusagalactiae; and the like. For such use, the halogenated derivatives canbe dispersed in water or oil with or without a wetting, dispersing oremulsifying agent in concentrations which can vary over a wide rangesuch as that of about 0.01% to 1% by weight of the water or oil toprepare germicidal solutions, suspensions or emulsions which can beused, e.g., by spraying, to inhibit the growth of microorganisms. Also,they can be used in such concentrations as preservatives, e.g., in fuelsand oils. For example, the aldehyde, 5-trifiuoromethyl-2-furfural;inhibited the growth of the above named organisms in a soy broth mediumat a concentration of 0.01%.

The aldehydes and ketones of this invention can be condensed withvarious hydrazines, hydrazides and hydroxylamines by methods well knownin the art to prepare antibacterial agents and growth promoting agentsfor veterinary animals. A typical method for preparing the hydrazine orhydrazide derivatives can be illustrated by the preparation of asemicarbazone of an aldehyde or ketone of this invention.Illustratively, to a solution of one molar equivalent of semicarbazidehydrochloride and one molar equivalent of sodium acetate dissolved inwater, is added one molar equivalent of an aldehyde or ketone of thisinvention, e.g., S-trifiuoromethyl-Z-furfural. The mixture is shakenvigorously for to minutes at room or elevated temperature and theresulting semicarbazone, e.g., S-trifluoromethyl-Z-furfuralsemicarbazone, forms as a precipitate. In place of the semicarbazidehydrochloride, other hydrazine or hydrazide reactants can be condensedwith aldehydes or ketones of this invention. Illustratively,hydroxylamine hydrochloride can be used to produce the correspondingthiosemicarbazone. The

hydrazine, hydrazide and hydroxylamine derivatives of the aldehydes andketones of this invention have antiprotazoal action. As describedhereinbefore the novel aldehydes and ketones have antibacterial action.As growth stimulants for veterinary animals, e.g., poultry and swine,the hydrazine, hydrazide and hydroxylamine derivatives of the novelaldehydes and ketones of this invention provide a growth improvement andenhanced feed efliciency through the administration of feedstuffcontaining a small quantity of such derivatives. For such use thehydrazine, hydrazide and hydroxylamine derivatives of the aldehydes andketones of this invention can be employed over a wide range ofconcentrations such as that of about 0.1 to 1000 grams thereof per tonof animal feed.

The trifluoromethyl group adds stability to the aldehydes and ketones ofthis invention. Thus, the heterocyclic ring is not subject to generalattack and degradation, as is generally found with the furan ring, e.g.,under acid conditions.

The following examples are illustrative of the invention:

Example 1.Preparation of ethyl 5-acetyl-2-trifiuoromethyl-3-furoate Asolution of sodium ethylate is prepared from 3.0 grams (g.) (0.1 g.atom) of sodium and 125 milliliters (ml.) of absolute ethanol.2-nitro-propane, 11.5 g. (0.13 mole), and 31.5 g. (0.1 mole) of ethyl5-(1-bromoethyl)- Z-trifiuoromethyl-3-furoate are added and the mixtureis stirred at room temperature for 20 hours. After removing the solventin vacuo, ml. water is added to the residue and the mixture is extractedwith ether. The organic extracts are washed with 18% sodium carbonatesolution then with water and dried over anhydrous magnesium sulfate.After filtration, the filtrate is concentrated in vacuo and the residueis purified by vapor phase chromatography (column) to give ethyl 5acetyI-Z-trifluoromethyl-3-furoate.

Example 2.Preparation of phenyl 5-formyl-2- trifiuoromethyl-3-furoate Asolution of sodium ethylate is prepared from 3.0 grams (g.) (0.1 g.atom) of sodium and milliliters (ml.) of absolute ethanol.2-nitro-propane, 11.5 g. (0.13 mole), and 34.9 g. (0.1 mole) of phenylS-bromomethyl- 2-trifluoromethyl-3-furoate are added and the mixture isstirred at room temperature for 20 hours. After removing the solvent invacuo, 100 ml. water is added to the residue and the mixture isextracted with ether. The organic extracts are washed with 18% sodiumcarbonate solution then with water and dried over anhydrous magnesiumsulfate. After filtration, th filtrate is concentrated in vacuo and theresidue is purified by vapor phase chromatography (column) to givephenyl 5 formyl 2 trifiuoromethyl-3-furoate.

Example 3.-Preparation of 4-carbethoxy-3-phenyl-5-trifluoromethylfurfural A solution of sodium ethylate is prepared from3.0 grams (g) (0.1 g. atom) of sodium and 125 milliliters (ml.) ofabsolute ethanol. 2-nitro-propane, 11.5 g. (0.13 mole), and 37.7 g. (0.1mole) of ethyl 5-bromomethyl-4- phenyl-2-trifluoromethyl-3-furoate areadded and the mixture is stirred at room temperature for 20 hours. Afterremoving the solvent in vacuo, 100 ml. water is added to the residue andthe mixture is extracted with ether. The organic extracts are washedwith 18% sodium carbonate solution then with water and dried overanhydrous magnesium sulfate. After filtration, the filtrate isconcentrated in vacuo and the residue is purified by vapor phasechromatography (column) to give 4-carbethoxy-3-phenyl-5-trifiuoromethylfurfural.

Example 4.Preparation of 4-carbethoxy-5- trifiuoromethyl-S-furfural Asolution of sodium ethylate is prepared from 3.0 grams (g.) (0.1 g.atom) of sodium and 125 milliliters (ml.) of absolute ethanol.2-nitro-propane, 11.5 g. (0.13 mole), and 30.1 g. (0.1 mole) of ethyl4-bromomethyl-2- trifluoromethyl-Ii-furoate are added and the mixture isstirred at room temperature for 20 hours. After removing the solvent invacuo, 100 ml. water is added to the residue and the mixture isextracted with ether. The organic extracts are washed with 18% sodiumcarbonate solution then with water and dried over anhydrous magnesiumsulfate. After filtration, the filtrate is concentrated in vacuo and theresidue is purified by vapor phase chromatography (column) to give 4carbethoxy 5 trifiuoromethyl-3-furfural.

Example 5.Preparation of 4-carbethoxy-2-phenyl-5-trifiuoromethyl-3-furfural A solution of sodium ethylate is preparedfrom 3.0 grams (g.) (0.1 g. atom) of sodium and 125 milliliters (ml.) ofabsolute ethanol. 2-nitro-propane, 11.5 g. (0.13 mole), and 37.7 g. (0.1mole) of ethyl 4-bromomethyl-5- phenyl-2-trifluoromethyl-3-furoate areadded and the mixture is stirred at room temperature for 20 hours. Afterremoving the solvent in vacuo, 100 ml. water is added to the residue andthe mixture is extracted with ether, The organic extracts are washedwith 18% sodium carbonate solution then with water and dried overanhydrous magnesium sulfate. After filtration, th filtrate isconcentrated in vacuo and the residue is purified by vapor phasechromatography (column) to give 4-carbethoxy-2-phenyl-5-trifiuoromethyl-3-furfural.

Example 6.Preparation of ethyl 4-acetyl-2- trifluoromethyl-3-furoate Asolution of sodium ethylate is prepared from 3.0 grams (g.) (0.1 g.atom) of sodium and 125 milliliters (ml.) of absolute ethanol.2-nitro-propane, 11.5 g. (0.13 mole), and 31.5 g. (0.1 mole) of ethyl4-(1-bromoethyl)-2-trifluoromethyl-3-furoate are added and the mixtureis stirred at room temperature for 20 hours. After removing the solventin vacuo, 100 ml. water is added to the residue and the mixture isextracted with ether. The organic extracts are washed with 18% sodiumcarbonate solution then with water and dried over anhydrous magnesiumsulfate. After filtration, the filtrate is concentrated in vacuo and theresidue is purified by vapor phase chromatography (column) to give ethyl4-acety1-2-trifluoromethyl-3-furoate.

Example 7.-Preparation of 2-acetyl-5- trifiuoromethylfuran A solution ofsodium ethylate is prepared from 3.0 grams (g.) (0.1 g. atom) of sodiumand 125 milliliters (ml.) of absolute ethanol. Z-nitro-propane, 11.5 g.(0.13 mole), and 24.3 g. (0.1 mole) ofZ-(bromoethyD-S-trifluoromethylfuran are added and the mixture isstirred at room temperature for 20 hours. After removing the solvent invacuo, 100 ml. water is added to the residue and the mixture isextracted with ether. The organic extracts are washed with 18% sodiumcarbonate solution then with water and dried over anhydrous magnesiumsulfate. After filtration, the filtrate is concentrated in vacuo and theresidue is purified by vapor phase chromatography (column) to give2-acetyl-S-trifluoromethylfuran.

Example 8.-Preparation of 3-phenyl-5-trifluoromethylfurfural A solutionof sodium ethylate is prepared from 3.0 grams (g.) (0.1 g. atom) ofsodium and 125 milliliters (ml.) of absolute ethanol. 2-nitro-propane,11.5 g. (0.13 mole), and 30.5 (0.1 mole) of 2-bromomethyl-3-phenyl-S-trifluoromethylfuran are added and the mixture is stirred at roomtemperature for 20 hours. After removing the solvent in vacuo, 100 ml.water is added to the residue and the mixture is extracted with ether.The organic extracts are washed with 18% sodium carbonate solution thenwith water and dried over anhydrous magnesium sulfate. After filtration,the filtrate is concentrated in vacuo and the residue is purified byvapor phase chromatography (column) to give 3-phenyltrifluoromethylfurfural.

Example 9.Preparation of 5-trifluoromethyl- 3-furfural A solution ofsodium ethylate is prepared from 3.0 grams (g.) (0.1 g. atom) of sodiumand 125 milliliters (ml.) of absolute ethanol. 2-nitro-propane, 11.5 g.(0.13 mole), and 22.9 g. (0.1 mole) of3-bromomethyl-5-trifiuoromethylfuran are added and the mixture isstirred at room temperature for hours. After removing the solvent invacuo, 100 ml. water is added to the residue and the mixture isextracted with ether. The organic extracts are washed with 18% sodiumcarbonate solution then with water and dried over anhydrous magnesiumsulfate.

After filtration, the filtrate is concentrated in vacuo and the residueis purified by vapor phase chromatography (column) to giveS-trifluoromethyl-B-furfural.

Example 10.Preparati0n of 2-phenyl-5-trifluoromethyl- B-furfural Asolution of sodium ethylate is prepared from 3.0 grams (g.) (0.1 g.atom) of sodium and milliliters (ml.) of absolute ethanol.2-nitro-propane, 11.5 g. (0.13 mole), and 30.5 g. (0.1 mole) of3-bromomethyl-2-phenyl-S-trifluoromethylfurfuran are added and themixture is stirred at room temperature for 20 hours. After removing thesolvent in vacuo, 100 ml. water is added to the residue and the mixtureis extracted with ether. The organic extracts are washed with 18% sodiumcarbonate solution then with water and dried over anhydrous magnesiumsulfate. After filtration, the filtrate is concentrated in vacuo and theresidue is purified by vapor phase chromatography (column) to give2-phenyl-5-trifiuoromethyl-3-furfural.

Example 11.Preparation of ethyl-S-acetyl-Z-trfluoromethyl-3-furoate Astirred mixture of 10 g. (0.1 mole) of calcium carbonate, 39.4 g. (0.1mole) of ethyl 5-(l,1-dibromoethyl)- 2-trifluoromethyl-3-furoate and 250ml. of Water is heated under reflux temperature for 16 hours. The cooledmixture is extracted three times with ISO-m1. portions of ether and thecombined extracts are dried over anhydrous magnesium sulfate. Afterfiltration, the solvent is removed at reduced pressure and the residueis purified by vapor phase chromatography (column) to give ethyl5-acetyl-2- trifiuoromethyl-3-furoate.

Example 12.Preparati0n of phenyl-S-formyl-Z-trifluoromethyl-3-furoate Astirred mixture of 10 g. (0.1 mole) of calcium carbonate, 42.8 g. (0.1mole) of phenyl S-dibromomethyl-Z- trifluoromethyl-3-furoate and 250 ml.of water is heated under reflux temperature for 16 hours. The cooledmixture is extracted three times with -ml. portions of ether and thecombined extracts are dried over anhydrous magnesium sulfate. Afterfiltration, the solvent is removed at reduced pressure and the residueis purified by vapor phase chromatography (column) to give phenyl5-formyl- 2-trifluoromethyl-3-furoate.

Example 13.-Preparation of 4-carbethoxy-3-phenyl-5-trifluoromethylfurfural A stirred mixture of 10 g. (0.1 mole) ofcalcium carbonate, 45.6 g. (0.1 mole) of ethyl 5-dibromomethyl-4-phenyl-2-trifluoromethyl-3-furoate and 250 m1. of water is heated underreflux temperature for 16 hours. The cooled mixture is extracted threetimes with 150-ml. portions of ether and the combined extracts are driedover anhydrous magnesium sulfate. After filtration, the solvent isremoved at reduced pressure and the residue is purified by vapor phasechromatography (column) to give4-carbethoxy-3-phenylS-trifluoromethylfurfural.

Example 14.Preparation of 4-carbethoxy-5-trifluoromethyl-3-furfural Astirred mixture of 10 g. (0.1 mole) of calcium carbonate, 38.0 g. (0.1mole) of ethyl 4-dibromomethyl-2-trifluoromethyl-3-furoate and 250 ml.of water is heated under reflux temperature for 16 hours. The cooledmixture is extracted three times with 150-ml. portions of ether and thecombined extracts are dried over anhydrous magnesium sulfate. Afterfiltration, the solvent is removed at reduced pressure and the residueis purified by vapor phase chromatography (column) to give4-carbethoxy-5- trifluoromethyl-3-furfural.

Example 15.Preparation of 4-carbethoxy-2-phenyl-5-trifluoromethyl-3-furfural A stirred mixture of 10 g. (0.1 mole) ofcalcium carbonate, 45.6 g. (0.1 mole) of ethyl 4-dibromomethyl-5-phenyl-2-trifluoromethyl-3-furoate and 250 ml. of water is heated underreflux temperature for 16 hours. The cooled mixture is extracted threetimes with ISO-ml. portions of ether and the combined extracts are driedover anhydrous magnesium sulfate. After filtration, the solvent isremoved at reduced pressure and the residue is purified by vapor phasechromatography (column) to give4-carbethoxy-2-phenyl-5-trifluoromethyl-3-furfural.

Example l6.Preparation of ethyl 4-acetyl-2- trifluoromethyl-3-furoate Astirred mixture of 10 g. (0.1 mole) of calcium carbonate, 39.4 g. (0.1mole) of ethyl 4-dibromomethyl- 2-trifluoromethyl-3-furoate and 250 ml.of water is heated under reflux temperature for 16 hours. The cooledmixture is extracted three times with ISO-ml. portions of ether and thecombined extracts are dried over anhydrous magnesium sulfate. Afterfiltration, the solvent is removed at reduced pressure and the residueis purified by vapor phase chromatography (column) to give ethyl4-acetyl-2-trifluoromethyl-3-furoate.

Example l7.Preparation of Z-acetyl- S-trifluoromethylfuran A stirredmixture of 10 g. (0.1 mole) of calcium carbonate, 32.2 g. of2-(1-,1-dibromomethyl)-5-trifiuoromethylfuran and 250 ml. of water isheated under reflux temperature for 16 hours. The cooled mixture isextracted three times with ISO-ml. portions of ether and the combinedextracts are dried over anhydrous magnesium sulfate. After filtration,the solvent is removed at reduced pressure and the residue is purifiedby vapor phase chromatography (column) to give 2-acetyl-5-trifluoromethylfuran.

Example 18.Preparation of 3phenyl-5- trifluoromethylfurfural A stirredmixture of 10 g. (0.1 mole) of calcium carbonate, 38.4 g. (0.1 mole) of2-dibromomethyl-3- phenyl-S-trifluoromethylfuran and 250 ml. of Water isheated under reflux temperature for 16 hours. The cooled mixture isextracted three times with 150-ml. portions of ether and the combinedextracts are dried over anhydrous magnesium sulfate. After filtration,the solvent is removed at reduced pressure and the residue is purifiedby vapor phase chromatography (column) to give 3-phenyl-S-trifluoromethylfurfural.

Example 19.-Preparation of 5- trifluoromethyl-3-furfural A stirredmixture of g. (0.1 mole) of calcium carbonate, 30.8 g. (0.1 mole) of3-dibromomethyl-5- trifluoromethylfuran and 250 ml. of water is heatedunder reflux temperature for 16 hours. The cooled mixture is extractedthree times with 150-ml. portions of ether and the combined extracts aredried over anhydrous magnesium sulfate. After filtration, the solvent isremoved at reduced pressure and the residue is purified by vapor phasechromatography (column) to give 5-trifluoromethyl-3-furfural.

Example 20.Preparation of 2-phenyl-5 trifluoromethyl-3-furfural Astirred mixture of 10 g. (0.1 mole) of calcium carbonate, 38.4 g. (0.1mole) of 3-dibromomethyl-2- phenyl-S-trifluoromethylfuran and 250 ml. ofwater is heated under reflux temperature for 16 hours. The cooledmixture is extracted three times with ISO-ml. portions of ether and thecombined extracts are dried over anhydrous magnesium sulfate. Afterfiltration, the solvent is 12 removed at reducted pressure and theresidue is purified by vapor phase chromatography (column) to give 2-phenyl-S-trifluoromethyl-3-furfural.

Example 2l.Preparation of 4-carbethoXy-5- trifluoromethyl-2-furfural Amixture of 20.0 g. of 5-dibromomethyl-3-carbethoxy-S-trifluoromethylfuran, 150 ml. water and 20.0 g. calcium carbonate washeated under reflux, with stirring, for 6.0 hours. The mixture wascooled and then extracted with ether. After drying the ether extractover magnesium sulfate, and removing the drying agent by filtration, thefiltrate was evaporated at reduced pressure to give 6.7 g. (53% yield of4 carbethoxy 5 trifluoromethyl 2- furfural.

Example 22.Preparation of S-trifluoromethyl- 2-furfural A mixture of22.9 g. of 5-trifluoromethyl-Z-bromomethylfuran, 14.0 g. ofhexamethylenetetramine and 150 ml. of chloroform was stirred for a fewhours and the hexamethylenetetraminium salt which formed was collectedby filtration, 34.7 g. (94% yield). The dried salt (22.0 g.) was thendisolved in 40 ml. of acetic acid and the solution was refluxed forthree hours. To the mixture was added 10 ml. of concentratedhydrochloric acid and the acidified solution was poured over ice water.The mixture was extracted three times with ether and the ether extractscombined and dried over anhydrous magnesium sulfate. Evaporation of theextract gave the crude S-trifluoromethyl-Z-furfural which was convertedto the semicarbazone by the usual procedure, wt. 2.2 g. (17% yield) M.P.208210. This type of aldehyde synthesis may also be carried out withoutisolation of the hexamethylene tetramine salt (see Org. Syn., vol. 8,pp. 197-217).

Example 23.-Preparation of S-trifluoromethyl- 2-furfural To 5.3 g. ofsodium in 300 ml. absolute alcohol was added 30 g. of 2-nitropropane. Tothe resulting solution was added, with stirring 55.3 g. ofZ-bromomethyl-S-trifluoromethyfuran. After stirring the mixture for 3hours at a temperature of the solvent was removed by evaporation atreduced pressure. Water was added to the residue and the mixtureextracted with ether. The ether phase was washed 2 times with -ml.portions of 5% aqueous sodium hydroxide and then with water. The etherplase was dried over magnesium sulfate and then the ether was removed bydistillation. Vacuum distillation (40 mm.) of the residue gave 18.8 g.,B.P. 68-70".

Analysis.--Cal. for C H F O C, 43.8; H, 1.84; F, 34.8. Found: C, 43.4;H, 1.84; F, 34.6.

Example 24.-Preparation of ethyl 2-formyl-5-trifluoromethyl-4-furoate To1.55 g. sodium dissolved in 65 ml. absolute ethanol was added 7.55 g. of2-nitr0propane. Next, was added 20 g. of ethyl5-bromomethyl-2-trifluoromethyl-3-furoate and the mixture was stirred atroom temperature for 20 hours. The ethanol was removed by evaporation atreduced pressure and water was added to the residue. The resultingmixture was extracted with ether. The ether phase was washed With sodiumcarbonate and then water. The ether phase was dried over magnesiumsulfate and then evaporated. The residual oil was distilled underreduced pressure (0.4 mm.) to give 11 g. of ethyl 2- wherein: one of R'and R is formyl and the remaining R or R" is a member selected from thegroup consisting of hydrogen, phenyl and naphthyl.

2. 5-trifiuoromethyl-2-furfural.

3. 5-trifiuoromethyl-3-phenyl-2-furfural.

4. A compound of the formula u R-OC-C(|f-R F e-o C-R" wherein R is amember selected from the group consisting of lower alkyl, cycloalkylhaving from 3 to 6 carbon atoms, phenyl, naphthyl, phenylalkyl having 7to 14 carbon atoms and naphthylalkyl having from 11 to 14 carbon atoms;one of R and R is formyl and the remaining R or R" is a member selectedfrom the group consistin g of hydrogen, phenyl and naphthyl.

5. A compound of claim 4 wherein R is lower alkyl, R is hydorgen and R"is formyl.

6. 4-carbethoxy-S-trifluoromethyl-Z-furfural.

7. Phenyl 5-formyl-Z-trifinoromethyl-3-furoate.

8. 4 carbethoxy-3-phenyl5-trifluoromethyl-Z-furfural.

9. A compound of the formula wherein one of R and R is alkylcarbonyl ofthe formula 0 H -CZ wherein Z is alkyl of 1 to 5 carbon atoms and theremaining R or R" is a member selected from the group consisting ofhydrogen, phenyl and naphthyl.

10. Z-acetyl-5-trifiuoromethy1furan.

11. A compound of the formula wherein R is a member selected from thegroup consisting of lower alkyl, cycloalkyl having from 3 to 6 carbonatoms, phenyl, naphthyl, phenylalkyl having from 7 to 14 carbon atomsand naphthlyalkyl having from 11 to 14 carbon atoms; one of R and :R" isalkylcarbonyl of the formula 0 I! -o z wherein Z is alkyl of 1 to 5carbon atoms and the remaining R or R is a member selected from thegroup consisting of hydrogen and carbocyclic aryl of 6 to 10 carbonatoms.

12. A compound of claim 11 wherein R is lower alkyl, R" is the group andR is hydrogen.

13. Ethyl-5-acetyl-2-trifluoromethyl-3-furoate.

References Cited UNITED STATES PATENTS 2,436,532 2/1948 Singleton260-347.3 2,744,917 5/1956 Jones et a1 260-347.5

OTHER REFERENCES Wertheim: Textbook of Organic Chemistry, pages 763 to764 (1945), second edition. QD251. W48.

Yale: 1 our. Med. Pharm. Chem, volume 1, No. 2, pages 121 to 131 (1959),RS115.

ALEX MAZEL, Primary Examiner.

B. I. DENTZ, Assistant Examiner.

US. Cl. X.R.

1. A COMPOUND OF THE FORMULA